Osteoporosis is a bone disorder characterized by the loss of bone mass, which leads to fragility and porosity of the bone of man. As a result, patients suffering from osteoporosis have an increased fracture risk of the bones. Postmenopausal women are particularly at risk for osteoporosis as a result of reduced levels of estrogen production. When administered at low levels, estrogens have a beneficial effect on the loss of bone. However, estrogen replacement therapy can have unwanted side effects including an increased risk of blood clots, breast carcinomas, endometrium hyperplasia, and an increased risk of endometrium carcinomas. The remaining current therapies provide little in terms of generating new bone for osteoporotic patients. Hence, a need exists for an alternative treatment of osteoporosis.
Sclerosteosis is a genetic disease resulting in increased bone formation and the development of strong skeletons in humans. Sclerosteosis is caused by a loss of function or null mutation in the SOST gene (Beighton et al. 1976; Brunkow et al. 2001; Balesman et al. 2001). The majority of affected individuals have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect. Homozygosity mapping in Afrikaner families along with analysis of historical recombinants localized sclerosteosis to an interval of approximately 2 cM between the loci D17S1787 and D17S930 on chromosome 17q12-q21. Affected Afrikaners carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries two splicing mutations within the single intron of the gene.
The SOST gene encodes a protein called sclerostin that shares some sequence similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte. The sclerostin protein gene is thought to interact with one or more of the bone morphogenetic proteins (BMPs) (Brunkow et al, 2001). Bone morphogenetic proteins are members of the transforming growth factor (TGF-β) superfamily that have been shown to play a role in influencing cell proliferation, differentiation and apoptosis of many tissue types including bone. Bone morphogenetic proteins can induce de novo cartilage and bone formation, and appear to be essential for skeletal development during mammalian embryogenesis (Wang 1993). Early in the process of fracture healing the concentration of bone morphogenetic protein-4 (BMP-4) increases dramatically (Nakase et al. 1994 and Bostrom et al. 1995). In vivo experiments indicate that up-regulation of BMP-4 transcription may promote bone healing in mammals (Fang et al. 1996). Bone morphogenetic proteins have been reported to induce the differentiation of cells of the mesenchymal lineage to osteogenic cells as well as to enhance the expression of osteoblastic phenotypic markers in committed cells (Gazzero et al. 1998, Nifuji & Noda, 1999). The activities of bone morphogenetic proteins in osteoblastic cells appear to be modulated by proteins such as noggin and gremlin that function as bone morphogenetic protein antagonists by binding and inactivating bone morphogenetic proteins (Yamaguchi et al. 2000).
However, the cascade of events leading to bone mineralization and the factors that control bone density are not completely understood. A need exists for factors that can modulate the differentiation of osteoblastic cells, promote bone mineralization and improve bone density.